Prostate Cancer
Conditions
Keywords
Recurrent PSA-only prostate cancer following prostatectomy
Brief summary
The purpose of this study is to describe the rate of 3-year progression free survival in men with recurrent PSA-only disease after prostatectomy, who receive combined apalutamide (ARN-509) and standard ADT with salvage radiation therapy followed by docetaxel, ADT, and apalutamide, AND who have had testosterone recovery to \>100 ng/dl at 36 months. The hypothesis is that AR inhibition with apalutamide added to standard salvage external beam radiation with androgen deprivation therapy, as well as the addition of 6 cycles of docetaxel, will further prolong progression free survival.
Interventions
DRUGApalutamide
240mg tablet daily for 36 weeks
ADT will consist of treatment with a GnRH agonist or antagonist per physician and institutional preference. Either leuprolide acetate (Lupron Depot, 22.5 mg or 45 mg IM), triptorelin pamoate (Trelstar, 11.25 mg or 22.5 mg IM), goserelin acetate (Zoladex, 10.8mg SC) or degarelix (Firmagon 120 mg or 240 mg SC) will be administered monthly, every 3 months, or every 6 months, depending on institutional standards, for 36 weeks total.
RADIATIONSalvage radiation therapy
On week 9 (+/- 28 days), subjects will begin salvage radiation therapy to the prostate bed. The total dose to the prostate bed must be 66-74 Gy in 1.8-2 Gy daily fractions over a total of 6-8 weeks
DRUGDocetaxel
About 4 weeks (+/- 2 weeks, pending recovery of adverse events from radiation to Grade 2 or less) after completing radiation, patients will start docetaxel 75mg/m2 intravenously, every 3 weeks for 6 cycles.
Sponsors
Andrew J. Armstrong, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically-confirmed diagnosis of prostate adenocarcinoma. Variants of prostate cancer, including neuroendocrine features and small cell carcinoma of the prostate, are not permitted. 2. Gleason sum of 7 (with pT3 disease or positive margins or positive nodes \[4 or fewer\]), 8, 9, or 10 based on the radical prostatectomy specimen 3. PSA relapse within 4 years of prostatectomy defined by persistently detectable or rising PSA after surgery. 4. Evidence of disease recurrence or progression as evidenced by a PSA \> 0.20. This requires 2 consecutive rises in PSA, at least 1 week apart, over the post-prostatectomy nadir OR one PSA value above 0.20 ng/mL IF the patient failed to achieve a post-prostatectomy nadir of \< 0.2 ng/mL. 5. Age ≥ 18 years 6. Karnofsky performance status ≥ 80 7. Adequate laboratory parameters * Adequate bone marrow function: ANC ≥1.5 x 109/L, Platelets ≥100 x 109/L, Hb \>9g/dL * AST/SGOT and ALT/SGPT ≤ 2.5 x Institutional Upper Limit of Normal (ULN) * Serum bilirubin ≤ 1.5 x Institutional ULN (In subjects with Gilbert's syndrome, if total bilirubin is \> 1.5xULN, measure direct and indirect bilirubin and patient is eligible if direct bilirubin ≤ 1.5xULN). * Glomerular filtration rate (either estimated or calculated from 24-hour urine collection) ≥ 45 mL/min * Serum potassium ≥3.5 mmol/L 8. A minimum of 4 weeks from any major surgery prior to Cycle 1 Day 1. 9. Ability to swallow, retain, and absorb oral medication. 10. Ability to understand and the willingness to sign a written informed consent document. 11. Must use a condom if having sex with a pregnant woman. 12. Male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration.
Exclusion criteria
1. Radiographic evidence of metastatic disease. Patients with node-positive disease (≤4 positive nodes) at the time of radical prostatectomy are eligible. Patients with pelvic nodes less than 1.5 cm by short axis at the time of screening are eligible. Patients with any enlarged lymph nodes in the retroperitoneum or above the aortic bifurcation or with pelvic nodes ≥ 1.5 cm must be excluded. 2. PSA ≥ 4.0 ng/mL. 3. Testosterone level ≤ 100 ng/dL. 4. More than 1 month of prior hormone exposure or hormone exposure within 30 days of enrollment (up to 1 month of prior LHRH agonist and/or anti-androgen therapy as neoadjuvant therapy prior to prostatectomy is allowed). Prior enzalutamide, apalutamide, ketoconazole, abiraterone, or TAK700 for prostate cancer are prohibited. Prior antiandrogen therapy (including but not limited to bicalutamide, flutamide, nilutamide, enzalutamide, and apalutamide) and prior estrogen therapy (including estrogen patch) are not allowed. All investigational agents are prohibited within 30 days of enrollment. 5. The following medications are prohibited within 2 weeks of enrollment and while on study drug: * 5 α-reductase inhibitors (finasteride, dutasteride); * Biologic or other agents with anti-tumor activity against prostate cancer; * Systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone; oPremedication with systemic glucocorticoids greater than the equivalent of 10 mg per day of prednisone is permitted prior to docetaxel infusions. * Androgens (testosterone, dihydroepiandrosterone \[DHEA\], etc.) 6. Prior immunotherapy including sipuleucel-T. 7. Prior systemic chemotherapy (docetaxel, cabazitaxel, estramustine, other cytotoxic agents) 8. History of solid organ or stem cell transplantation. 9. History of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, prior head or traumatic brain injury with loss of consciousness, prior or current space-occupying lesion in the brain). Also, history of loss of consciousness or transient ischemic attack within 12 months of Day 1 visit. 10. Known or suspected brain metastasis or active leptomeningeal disease. 11. Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol. 12. Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to enrollment 13. Sustained uncontrolled hypertension (\>150/90 average over 1 week) despite optimal medical management 14. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of apalutamide or increase the risk of radiation (e.g., uncontrolled nausea, vomiting, diarrhea, malabsorption syndromes, prior small bowel resection, or inflammatory bowel disease). 15. Patients who have received prior prostate or pelvic radiotherapy, including external beam or brachytherapy. 16. Patients who have not recovered from side effects of prior systemic therapy prior to Cycle 1 Day 1. 17. Use of medications known to lower the seizure threshold within 4 weeks prior to study entry. 18. Patients unable or unwilling to abide by the study protocol or cooperate fully with the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) at 36 Months (3 Years) | up to 36 months | The percentage of subjects with testosterone \>100 ng/dl at 36 months post-Cycle 1 Day 1 without one or more of the following: Serum PSA value of 0.2 ng/mL or more above the post-radiotherapy PSA nadir and confirmed (at least) 4 weeks later by a second PSA measurement higher than the first by any amount; Continued rise in the PSA level following study treatment if no nadir is experienced, defined as 2 rising values greater than the baseline PSA and separated by at least 4 weeks; Evidence of clinical progression or initiation of systemic therapy for progressive disease; Death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a PSA of <0.1 ng/mL and Testosterone Recovery at 24 Months Post-Cycle 1 Day 1 | 24 months | Testosterone recovery defined as testosterone \>100 ng/dl |
| Percentage of Participants With a PSA of <0.1 ng/mL and Testosterone Recovery at 36 Months Post-Cycle 1 Day 1 | 36 months | Testosterone recovery defined as testosterone \>100 ng/dl |
| Biochemical Progression-free Survival (PFS) at 36 Months (3 Years) | 36 months | Percentage of participants still alive without disease progression based on PSA (prostate-specific antigen) only. Must have serum PSA value of 0.2 ng/mL or more above the post-radiotherapy PSA nadir and confirmed (at least) 4 weeks later by a second PSA measurement higher than the first by any amount. |
| Number of Participants With a PSA of <0.1 ng/mL and Testosterone Recovery at 12 Months Post-Cycle 1 Day 1 | 12 months | Testosterone recovery defined as testosterone \>100 ng/dl |
| Time to Testosterone Recovery | up to 36 months | Testosterone recovery defined as testosterone \>100 ng/dl |
| Percentage of Participants With Adverse Events as Assessed by CTCAE v4.0 | up to 36 months | To describe the safety, feasibility and tolerability profile of combination apalutamide, ADT, and radiation therapy followed by apalutamide, ADT, and docetaxel as assessed by NCI common toxicity scales |
| Percentage of Participants Completing All Treatments | 36 months | To describe the percentage of participants completing all treatments including salvage radiation therapy and 6 cycles of docetaxel |
| Median PSA Nadir Value | 36 months | Median PSA nadir value |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Recurrent PSA-only Non-metastatic Prostate Cancer Subjects with recurrent PSA-only prostate cancer within 4 years of prostatectomy, and a PSA of greater than 0.2 ng/mL and less than 4 ng/mL in the absence of metastatic disease on CT and bone scans.
Apalutamide: 240mg tablet daily for 36 weeks
Androgen deprivation: ADT will consist of treatment with a GnRH agonist or antagonist per physician and institutional preference. Either leuprolide acetate (Lupron Depot, 22.5 mg or 45 mg IM), triptorelin pamoate (Trelstar, 11.25 mg or 22.5 mg IM), goserelin acetate (Zoladex, 10.8mg SC) or degarelix (Firmagon 120 mg or 240 mg SC) will be administered monthly, every 3 months, or every 6 months, depending on institutional standards, for 36 weeks total.
Salvage radiation therapy: On week 9 (+/- 28 days), subjects will begin salvage radiation therapy to the prostate bed. The total dose to the prostate bed must be 66-74 Gy in 1.8-2 Gy daily fractions over a total of 6-8 weeks
Docetaxel: About 4 weeks (+/- 2 weeks, pending recovery of adverse events from radiation to Grade 2 or less) after completing radiation, patients will start docetaxel 75mg/m2 intravenously, every 3 weeks for 6 cycles. | 39 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Recurrent PSA-only Non-metastatic Prostate Cancer |
|---|---|
| Age, Continuous | 63.2 years STANDARD_DEVIATION 6.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 37 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 34 Participants |
| Region of Enrollment United States | 39 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 39 |
| other Total, other adverse events | 39 / 39 |
| serious Total, serious adverse events | 4 / 39 |
Outcome results
Primary
Progression-free Survival (PFS) at 36 Months (3 Years)
The percentage of subjects with testosterone \>100 ng/dl at 36 months post-Cycle 1 Day 1 without one or more of the following: Serum PSA value of 0.2 ng/mL or more above the post-radiotherapy PSA nadir and confirmed (at least) 4 weeks later by a second PSA measurement higher than the first by any amount; Continued rise in the PSA level following study treatment if no nadir is experienced, defined as 2 rising values greater than the baseline PSA and separated by at least 4 weeks; Evidence of clinical progression or initiation of systemic therapy for progressive disease; Death
Time frame: up to 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent PSA-only Non-metastatic Prostate Cancer | Progression-free Survival (PFS) at 36 Months (3 Years) | 69.2 percentage of participants |
Secondary
Biochemical Progression-free Survival (PFS) at 36 Months (3 Years)
Percentage of participants still alive without disease progression based on PSA (prostate-specific antigen) only. Must have serum PSA value of 0.2 ng/mL or more above the post-radiotherapy PSA nadir and confirmed (at least) 4 weeks later by a second PSA measurement higher than the first by any amount.
Time frame: 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent PSA-only Non-metastatic Prostate Cancer | Biochemical Progression-free Survival (PFS) at 36 Months (3 Years) | 69.2 percentage of participants |
Secondary
Median PSA Nadir Value
Median PSA nadir value
Time frame: 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recurrent PSA-only Non-metastatic Prostate Cancer | Median PSA Nadir Value | NA ng/mL |
Secondary
Number of Participants With a PSA of <0.1 ng/mL and Testosterone Recovery at 12 Months Post-Cycle 1 Day 1
Testosterone recovery defined as testosterone \>100 ng/dl
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Recurrent PSA-only Non-metastatic Prostate Cancer | Number of Participants With a PSA of <0.1 ng/mL and Testosterone Recovery at 12 Months Post-Cycle 1 Day 1 | 38 Participants |
Secondary
Percentage of Participants Completing All Treatments
To describe the percentage of participants completing all treatments including salvage radiation therapy and 6 cycles of docetaxel
Time frame: 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent PSA-only Non-metastatic Prostate Cancer | Percentage of Participants Completing All Treatments | 97.4 percentage of participants |
Secondary
Percentage of Participants With Adverse Events as Assessed by CTCAE v4.0
To describe the safety, feasibility and tolerability profile of combination apalutamide, ADT, and radiation therapy followed by apalutamide, ADT, and docetaxel as assessed by NCI common toxicity scales
Time frame: up to 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent PSA-only Non-metastatic Prostate Cancer | Percentage of Participants With Adverse Events as Assessed by CTCAE v4.0 | 100 percentage of participants |
Secondary
Percentage of Participants With a PSA of <0.1 ng/mL and Testosterone Recovery at 24 Months Post-Cycle 1 Day 1
Testosterone recovery defined as testosterone \>100 ng/dl
Time frame: 24 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent PSA-only Non-metastatic Prostate Cancer | Percentage of Participants With a PSA of <0.1 ng/mL and Testosterone Recovery at 24 Months Post-Cycle 1 Day 1 | 67 percentage of participants |
Secondary
Percentage of Participants With a PSA of <0.1 ng/mL and Testosterone Recovery at 36 Months Post-Cycle 1 Day 1
Testosterone recovery defined as testosterone \>100 ng/dl
Time frame: 36 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recurrent PSA-only Non-metastatic Prostate Cancer | Percentage of Participants With a PSA of <0.1 ng/mL and Testosterone Recovery at 36 Months Post-Cycle 1 Day 1 | 69 percentage of participants |
Secondary
Time to Testosterone Recovery
Testosterone recovery defined as testosterone \>100 ng/dl
Time frame: up to 36 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recurrent PSA-only Non-metastatic Prostate Cancer | Time to Testosterone Recovery | 15 months |